Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders

ABSTRACT

Disclosed herein are methods of treating conditions, which may be associated with elevated levels of plasma cells and/or B-cells, with a therapeutically effective amount of dexpramipexole or pharmaceutical acceptable salt thereof.

This application is a continuation application of U.S. application Ser.No. 14/912,058 filed Feb. 12, 2016, now U.S. Pat. No. 9,642,840 issuedon May 9, 2017, which is a national stage application ofPCT/US2014/050943 filed Aug. 13, 2014, which claims priority to U.S.Provisional Application No. 61/865,592 filed Aug. 13, 2013 and to U.S.Provisional Application No. 61/987,117 filed on May 1, 2014, which arehereby incorporated herein by reference in their entireties.

SUMMARY

Embodiments of the present invention relate to a method of treating aplasma cell disorder characterized by elevated levels of plasma cells inthe bone marrow in a subject by administering to a subject in needthereof, a therapeutically effective amount of dexpramipexole. In someembodiments, the condition is further characterized by the presence ofserum monoclonal proteins in the subject. The condition may be furthercharacterized by an increase in monoclonal proteins in the peripheralblood of the subject. The condition may be even further characterized bybone and kidney dysfunction. In some embodiments, the condition ismonoclonal gammopathy of undetermined significance. In otherembodiments, the condition is multiple myeloma.

Various embodiments may relate to a method of treating a plasma celldisorder where the elevated levels of plasma cells may be characterizedas greater than 10% of total cells in the bone marrow. In otherembodiments, the elevated levels of plasma cells may be characterized asgreater than 30% of total cells in the bone marrow.

In some embodiments, the therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 1 mg to about 1,000 mg per day. In some embodiments, thetherapeutically effective amount may be from about 50 mg to about 600 mgper day. In some embodiments, the therapeutically effective amount maybe from about 150 mg to about 300 mg per day. In some embodiments, thetherapeutically effective amount may be at least about 150 mg. In someembodiments, the therapeutically effective amount may be at least about300 mg. In some embodiments, the therapeutically effective amount may beat least about 150 mg. In some embodiments, the therapeuticallyeffective amount may be at least about 1200 mg. In some embodiments, thetherapeutically effective amount may be at least about 1500 mg.

In some embodiments, administering a therapeutically effective amountcomprises administering a daily dose as a fraction of the daily dose (asdescribed herein) two or more times per day. In some embodiments,administering a therapeutically effective amount comprises administeringa dose equal to about half of a daily dose twice per day. In someembodiments, the dose may be administered every about 12 hours. In someembodiments, administering a therapeutically effective amount comprisesadministering about 150 mg two times per day.

Some embodiments further comprise administering to the subject atherapeutically effective amount of one or more secondary agentsselected from a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), intravenous immunoglobulin, a tyrosine kinase inhibitor, afusion protein, a monoclonal antibody directed against one or morepro-inflammatory cytokines, a chemotherapeutic agent, or a combinationthereof.

Some embodiments further comprise administering simultaneously orconcurrently with one or more other treatments.

Various embodiments may also comprise an induction step. In someembodiments, said induction step comprises administering to said subjecta therapeutically effective amount of a secondary agent capable ofdecreasing levels of plasma cells and/or B-cell prolymphocytes in thesubject prior to administration of a therapeutically effective amount ofdexpramipexole. In some embodiments, the secondary agent isdexpramipexole. In some embodiments, the secondary agent is selectedfrom a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), atyrosine kinase inhibitor, a fusion protein, a monoclonal antibodydirected against one or more pro-inflammatory cytokines, achemotherapeutic agent, or a combination thereof. In some embodiments,said induction step comprises administering a therapeutically effectiveamount of a secondary agent for a period of about 1 day to about 6months. In some embodiments, said induction step comprises administeringa therapeutically effective amount of a secondary agent for a period ofabout 1 week to about 4 months.

Embodiments of the present invention relate to a method of treating aB-cell disorder characterized by elevated levels of B-cells in a subjectby administering to a subject in need thereof, a therapeuticallyeffective amount of dexpramipexole. In some embodiments, the conditionmay be further characterized by elevated levels of B-cell prolymphocytesin the peripheral blood. In further embodiments, the elevated levels ofB-cell prolymphocytes may be greater than 15% in the peripheral blood.

In some embodiments, the therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 1 mg to about 1,000 mg per day. In some embodiments, thetherapeutically effective amount may be from about 50 mg to about 600 mgper day. In some embodiments, the therapeutically effective amount maybe from about 150 mg to about 300 mg per day. In some embodiments, thetherapeutically effective amount may be at least about 150 mg. In someembodiments, the therapeutically effective amount may be at least about300 mg. In some embodiments, the therapeutically effective amount may beat least about 150 mg. In some embodiments, the therapeuticallyeffective amount may be at least about 1200 mg. In some embodiments, thetherapeutically effective amount may be at least about 1500 mg.

In some embodiments, administering a therapeutically effective amountcomprises administering a daily dose as a fraction of the daily dose (asdescribed herein) two or more times per day. In some embodiments,administering a therapeutically effective amount comprises administeringa dose equal to about half of a daily dose twice per day. In someembodiments, the dose may be administered every about 12 hours. In someembodiments, administering a therapeutically effective amount comprisesadministering about 150 mg two times per day.

Some embodiments further comprise administering to the subject atherapeutically effective amount of one or more secondary agentsselected from a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), intravenous immunoglobulin, a tyrosine kinase inhibitor, afusion protein, a monoclonal antibody directed against one or morepro-inflammatory cytokines, a chemotherapeutic agent, or a combinationthereof.

Some embodiments further comprise administering simultaneously orconcurrently with one or more other treatments.

Various embodiments may also comprise an induction step. In someembodiments, said induction step comprises administering to said subjecta therapeutically effective amount of a secondary agent capable ofdecreasing levels of plasma cells and/or B-cell prolymphocytes in thesubject prior to administration of a therapeutically effective amount ofdexpramipexole. In some embodiments, the secondary agent isdexpramipexole. In some embodiments, the secondary agent is selectedfrom a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), atyrosine kinase inhibitor, a fusion protein, a monoclonal antibodydirected against one or more pro-inflammatory cytokines, achemotherapeutic agent, or a combination thereof. In some embodiments,said induction step comprises administering a therapeutically effectiveamount of a secondary agent for a period of about 1 day to about 6months. In some embodiments, said induction step comprises administeringa therapeutically effective amount of a secondary agent for a period ofabout 1 week to about 4 months.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the dose- and time-dependent effects of dexpramipexole oneosinophil counts from minipigs. The reduction of eosinophils wasobserved in minipigs in long-term toxicity studies (n=5-9 dosegroup/treatment interval).

FIG. 2A depicts the dose-dependent effect of dexpramipexole oneosinophil counts in the Phase 2 trial CL201 (n=22-25 per group). InFIG. 2A the time period marked “W” represents the end of the 4-weekwashout following the month 3 time point. FIG. 2B depicts thetime-dependent effect of dexpramipexole on eosinophil counts in thePhase 3 trial EMPOWER. (Mean±SEM, N=474 at baseline, N=328 at 12 monthsin dexpramipexole group, 467 and 340 in placebo group).

FIG. 3A depicts the time-dependent effects of dexpramipexole onbasophils in the Phase 3 trial. FIG. 3B depicts the effects ofdexpramipexole on neutrophils basophils in the Phase 3 trial. (Mean±SEM,N=474 at baseline in dexpramipexole group, 468 in placebo group).

FIG. 4A shows that dexpramipexole decreases eosinophils in a subject inthe Phase 2 study with a high baseline eosinophil count. FIG. 4B showsthat dexpramipexole decreases eosinophils in a subject in the Phase 3trial with a high baseline eosinophil count.

FIG. 5 shows the change in complete blood counts (CBC) in dexpramipexoleand placebo groups from baseline to month 6 in the Phase 3 trial.

FIG. 6A shows the effects of dexpramipexole on the cell numbers for cellsurface marker Scar c-Kit⁺ cells that are lineage negative in the bonemarrow of BalbC wild type mice for the three study groups. FIG. 6B showsthe effects of dexpramipexole on the Siglec-F¹⁰ IL5Rα^(hi) positive cellnumbers in the bone marrow of BalbC wild type mice for the three studygroups.

DETAILED DESCRIPTION

Plasma cell diseases have various characteristics used to classify eachdisease. For example, multiple myeloma (also known as myeloma or plasmacell myeloma) is a progressive hematologic disease, characterized byexcessive levels of abnormal plasma cells (multiple myeloma plasmacells) in the bone marrow and overproduction of intact monoclonalimmunoglobulin. It is thought that multiple myeloma may arise from acommon benign plasma cell tumor called Monoclonal Gammopathy ofUndetermined Significance (MGUS). Multiple myeloma accounts for 1% ofall cancers and 10% of all hematologic malignancies (making it thesecond most common hematological malignancy) and 2% of all cancerdeaths. In multiple myeloma patients, mutated plasma cells growunregulated by the processes that normally control cell division anddeath. The interaction of cytokines such as interleukin (IL)-6 and tumornecrosis factor (TNF), stimulate the growth of myeloma cells and inhibitapoptosis, leading to proliferation of myeloma cells. Myeloma plasmacells have specific adhesion molecules on their surface allowing them toattach to bone marrow stromal cells. Thus, myeloma cells travelingthrough the bloodstream can collect in the bone marrow where theyinterfere with cells in the bone that produce white and red blood cellsand platelets, often causing anemia and a decreased immune function. Theovergrowth of plasma cells in the bone marrow often leads to structuralbone damage, resulting in bone pain and fractures. Myeloma cells alsoproduce abnormal antibodies that cannot effectively fight infection. Astumors grow they invade the hard, outer part of the bone, eventuallyspreading into the bone marrow of all the large bones of the body, withmyeloma cells found in multiple sites throughout the bone marrow. Thediagnosis of multiple myeloma requires (i) 10% or more clonal plasmacells on bone marrow examination or a biopsy-proven plasmacytoma, plus(ii) evidence of end-organ damage felt to be related to the underlyingplasma cell disorder. Multiple myeloma is characterized by markedgenetic heterogeneity with two broad genetic subtypes defined bychromosome number, namely, hyperdiploid multiple myeloma andnonhyperdiploid multiple myeloma. The latter is associated with primaryIgH translocations including (I 1;14)(ql3;q32) and t(4;14)(pl6;q32),respectively representing 20% and 15% of multiple myeloma cases. It hasbeen shown that multiple myeloma patients with the chromosomalabnormality t(4;14) have a poor prognosis and poor overall survival withaggressive relapse and short remission times even following a positiveresponse to stem cell transplantation.

As described above, in multiple myeloma, multiple myeloma plasma cellsare cradled within the bone marrow microenvironment by an array ofadhesive interactions between the bone marrow cellular residents, thesurrounding extracellular matrix components such as fibronectin, lamin,vascular cell adhesion molecule-1 (VCAM-1), proteoglycans, collagens,and hyaluron as well as a variety of adhesion molecules on the surfaceof the multiple myeloma plasma cells including integrins, hyaluronreceptors (CD44 and RHAMM) and heparin sulfate proteoglycans. Severalsignaling responses are activated in these interactions, affecting thesurvival, proliferation and migration of multiple myeloma plasma cells.An important consequence of these direct adhesive interactions betweenthe bone marrow and/or the extracellular matrix and the multiple myelomaplasma cells is the development of drug resistance. This phenomenon istermed “cell adhesion-mediated drug resistance” (CAM-DR) and it isthought to be one of the major mechanisms by which multiple myelomaplasma cells escape the cytotoxic effects of therapeutic agents.

Eosinophils are white blood cells of myeloid lineage shown to reside inbone marrow niches in which plasma cells develop. In co-cultures ofhuman tissues, eosinophils have been shown to enhance the proliferationof malignant plasma cells. Bone marrow biopsies from multiple myelomapatients show that the percentage of eosinophils in close proximity tomultiple myeloma cells in the bone marrow increases with diseaseprogression. In eosinophil deficient mice, plasma cell accumulation inthe bone marrow is impaired and eosinophil depletion induces plasma cellapoptosis.

NJ1638 IL-5 transgenic hypereosinophilic mice have a B-celllymphocytosis that is nearly abolished following genetic deletion oftheir eosinophils. In vitro studies using human tissues havedemonstrated eosinophils' proximity to B-cell follicles and theirability to promote B-cell survival, proliferation, and Ig secretion viaa contact-independent mechanism. In hypereosinophilic patients, there isdirect correlation between peripheral blood eosinophil levels and B-cellnumbers.

Basophils are also white blood cells of myeloid lineage that reside inthe bone marrow. In addition to supporting B-cell responses, basophilshave been shown to support the survival of plasma cells. In vitro, theabsence of basophils has been shown to cause the rapid death of isolatedplasma cells, while the addition of basophils enabled their survival. Inmice, the presence of basophils in bone marrow has been shown to supportplasma call survival.

Plasma cells are antibody-secreting cells found in lymphoid tissue andderived from B-cells upon lymphokine stimulation and reaction with aspecific antigen. Without wishing to be bound to theory, it is believedthat decreasing eosinophils may result in a decrease in plasma celllevels, B-cell levels, or a combination thereof. It has recently beendemonstrated that eosinophils have the ability to induce malignant humanplasma cells proliferation. It has also been reported thathypereosinophilic (NJ1638) mice, which constitutively express the IL-5transgene, exhibit B-cell lymphocytosis that can be ameliorated viaremoval of eosinophils from these mice. Human in vitro studies haveshown that purified eosinophils can enhance B-cell proliferation whichmay involve both contact-dependent and -independent mechanisms. Therequirement of only a transient interaction between eosinophils andB-cells to result in augmented B-cell proliferation mimics the in vivodeparture of B-cells from the eosinophils at the T-B border uponactivation followed by germinal center formation.

Agents that selectively reduce plasma cell count and/or function, B-cellcount and/or function, or a combination thereof might be expected tobenefit patients with multiple myeloma and other conditions associatedwith elevated levels of plasma cells, B-cells or a combination thereof.

Accordingly, a major need exists for a small molecule agent withestablished preclinical and clinical safety experience for the treatmentof conditions associated with elevated levels of plasma cells and/orB-cells.

Dexpramipexole ((6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole), is a synthetic aminobenzothiazole derivative with thefollowing structure:

As used herein, dexpramipexole may be administered as a free base of apharmaceutical acceptable salt. Pharmaceutical acceptable salts include,but are not limited to, any acid addition salt, preferably apharmaceutically acceptable acid addition salt, including, but notlimited to, halogenic acid salts such as hydrobromic, hydrochloric,hydrofloric and hydroiodic acid salt; an inorganic acid salt such as,for example, nitric, perchloric, sulfuric and phosphoric acid salt; anorganic acid salt such as, for example, sulfonic acid salts(methanesulfonic, trifluoromethan sulfonic, ethanesulfonic,benzenesulfonic or p-toluenesufonic, acetic, malic, fumaric, succinic,citric, benzonic gluconic, lactic, mandelic, mucic, pamoic, pantothenic,oxalic and maleic acid salts; and an amino acid salt such as aspartic orglutamic acid salt. The acid addition salt may be a mono- or di-acidaddition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric ordi-organic acid salt. In all cases, the acid addition salt is used as anachiral reagent which is not selected on the basis of any expected orknown preference for the interaction with or precipitation of a specificoptical isomer of the products of this disclosure.

As dexpramipexole was well-tolerated in humans following exposures up to18 months, it may represent a novel therapeutic approach for thetreatment of conditions associated with elevated levels of plasma cellsand/or B-cells.

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the exemplary methods, devices, and materialsare now described.

In each of the embodiments described herein, the method may compriseadministering a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof. In each of the embodimentsdescribed herein, the method may consist essentially of administering atherapeutically effective amount of dexpramipexole or a pharmaceuticallyacceptable salt thereof. In each of the embodiments described herein,the method may consist of administering a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof.The term “comprising” means “including, but not limited to.” The term“consisting essentially of” means the method or composition includes thesteps or components specifically recited, and may also include thosethat do not materially affect the basic and novel characteristics of thepresent invention. The term “consisting of” means the method orcomposition includes only the steps or components specifically recited.

In each of the embodiments disclosed herein, the compounds and methodsmay be utilized with or on a subject in need of such treatment, whichmay also be referred to as “in need thereof” As used herein, the phrase“in need thereof” means that the subject has been identified as having aneed for the particular method or treatment and that the treatment hasbeen given to the subject for that particular purpose.

As used herein, the term “patient” and “subject” are interchangeable andmay be taken to mean any living organism, which may be treated withcompounds of the present invention. As such, the terms “patient” and“subject” may include, but is not limited to, any non-human mammal,primate or human. In some embodiments, the “patient” or “subject” is anadult, child, infant, or fetus. In some embodiments, the “patient” or“subject” is a human. In some embodiments, the “patient” or “subject” isa mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, primates, or humans.

As used herein, the term “plasma cell” refers to an antibody-secretingcell that is derived from a B-cell. In some embodiments, the term“plasma cell” refers to an antibody-secreting cell that reacts with anantigen. In some embodiments, the term “plasma cell” refers to a plasmaB-cell. In some embodiments, the term “plasma cell” refers to aneffector B-cell. In some embodiments, the term “plasma cell” refers to aplasmocyte. In some embodiments, the term “plasma cell” refers to aplasma cell or clonal plasma cell residing in the bone marrow, in thesystemic circulatory system, and/or in organ tissues. In someembodiments, the organ tissue is the bone, the kidney, lymph nodes, orcombinations thereof.

As used herein, the term “B-cell” refers to a lymphocyte. In someembodiments, the term “B-cell” refers B lymphocytes. In someembodiments, the term “B-cell” refers to a B-cell residing in the bonemarrow, in the systemic circulatory system, and/or in organ tissues. Insome embodiments, the organ tissue is the bone, the kidney, lymph nodes,or combinations thereof.

As used herein, a condition characterized by elevated levels of plasmacells and/or B-cells in a subject refers to a condition in which thenumbers of plasma cells and/or B-cells, as the case may be, areincreased or raised compared with a normal subject or are increased orraised compared to another subject with the same condition.

As used herein, the terms “adjunctive administration” and “adjunctively”may be used interchangeably, and refer to simultaneous administration ofmore than one compound in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration ofmore than one compound as part of a single therapeutic regimen.

As used herein, the term “antibody” may be used to include antibody andantibody fragments such as, Fab, Fab′, F(ab′)2, scFv, dsFv, ds-scFv,dimers, minibodies, diabodies, bispecific antibody fragments, multimers,and any combination thereof, and fragments from recombinant sourcesand/or produced in transgenic animals. The antibody or fragment may befrom any species including mice, rats, rabbits, hamsters and humans.Chimeric antibody derivatives, i.e., antibody molecules that combine anon-human animal variable region and a human constant region are alsocontemplated within the scope of the invention. Chimeric antibodymolecules may include, for example, humanized antibodies which comprisethe antigen binding domain from an antibody of a mouse, rat, or otherspecies, with human constant regions. Conventional methods may be usedto make chimeric antibodies. It is expected that chimeric antibodieswould be less immunogenic in a human subject than the correspondingnon-chimeric antibody.

As used herein, the term “a no observable adverse effect level” (NOAEL)dose refers to an amount of active compound or pharmaceutical agent thatproduces no statistically, clinically or biologically significantincreases in the frequency or severity of adverse effects between anexposed population and its appropriate control; some effects may beproduced at this level, but they are not considered as adverse, or asprecursors to adverse effects. The exposed population may be a system,tissue, animal, individual or human being treated by a researcher,veterinarian, medical doctor, or other clinician.

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.Moreover, the processes, compositions, and methodologies described inparticular embodiments are interchangeable. Therefore, for example, acomposition, dosages regimen, route of administration, and so ondescribed in a particular embodiments may be used in any of the methodsdescribed in other particular embodiments. It is also to be understoodthat the terminology used in the description is for the purpose ofdescribing the particular versions or embodiments only, and is notintended to the limit the scope of the present invention which will belimited only by the appended claims. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of the ordinary skill in the art. Althoughany methods similar or equivalent to those describe herein can be usedin the practice or testing of embodiments of the present invention, thepreferred methods are now described. All publications and referencesmentioned herein are incorporated by reference. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

It must be noted that, as used herein, and in the appended claims, thesingular forms “a”, “an” and “the” include plural reference unless thecontext clearly dictates otherwise.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the described includes instances where the event occurs andinstances where it does not.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly or indirectly into or onto a targettissue to administer a therapeutic to a patient whereby the therapeuticpositively impacts the tissue to which it is targeted. “Administering” acomposition may be accomplished by oral administration, injection,infusion, inhalation, absorption or by any method in combination withother known techniques. “Administering” may include the act ofself-administration or administration by another person such as a healthcare provider.

The term “improves” is used to convey that the present invention changeseither the appearance, form, characteristics, structure, function and/orphysical attributes of the tissue to which it is being provided, appliedor administered. “Improves” may also refer to the overall physical stateof an individual to whom an active agent has been administered. Forexample, the overall physical state of an individual may “improve” ifone or more symptoms of the disease, condition or disorder arealleviated by administration of an active agent.

As used here, the term “therapeutic” means an agent utilized to treat,combat, ameliorate or prevent an unwanted disease, condition or disorderof a patient.

The terms “therapeutically effective amount” or “therapeutic dose” isused herein are interchangeable and may refer to the amount of an activeagent or pharmaceutical compound or composition that elicits a clinical,biological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinical professional. A clinical, biological or medicalresponse may include, for example, one or more of the following: (1)preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display pathology or symptoms of the disease, condition ordisorder, (2) inhibiting a disease, condition or disorder in anindividual that is experiencing or displaying the pathology or symptomsof the disease, condition or disorder or arresting further developmentof the pathology and/or symptoms of the disease, condition or disorder,and (3) ameliorating a disease, condition or disorder in an individualthat is experiencing or exhibiting the pathology or symptoms of thedisease, condition or disorder or reversing the pathology and/orsymptoms experience or exhibited by the individual.

The term “treating” may be taken to mean prophylaxis of a specificdisorder, disease or condition, alleviation of the symptoms associatedwith a specific disorder, disease or condition and/or prevention of thesymptoms associated with a specific disorder, disease or condition. Insome embodiments, the term refers to slowing the progression of thedisorder, disease or condition or alleviating the symptoms associatedwith the specific disorder, disease or condition. In some embodiments,the term refers to alleviating the symptoms associated with the specificdisorder, disease or condition. In some embodiments, the term refers toalleviating the symptoms associated with the specific disorder, diseaseor condition. In some embodiments, the term refers to restoring functionwhich was impaired or lost due to a specific disorder, disorder orcondition.

As used herein, the terms “enantiomers,” “stereoisomers,” and “opticalisomers may be used interchangeably and refer to molecules which containan asymmetric or chiral center and are mirror images of one another.Further, the terms “enantiomers,” “stereoisomers,” or “optical isomers”describe a molecule which, in a given configuration, cannot besuperimposed on its mirror images.

As used herein, the terms “optically pure” or “enantiomerically pure”may be taken to indicate that a composition contains at least 99.95% ofa single optical isomer of a compound. The term “enantiomericallyenriched” may be taken to indicate that a least 51% of a composition ina single optical isomer or enantiomer. The term “enantiomericenrichment” as used herein refer to an increase in the amount of oneenantiomer as compared to the other. A “racemic” mixture is a mixture ofabout equal amounts of (6R) and (6S) enantiomers of a chiral molecule.

Throughout this disclosure, the word “pramipexole” will refer to (6S)enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazoleunless otherwise specified.

The term “pharmaceutical composition” shall mean a composition includingat least one active ingredient, whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, without limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan. A pharmaceuticalcomposition may, for example, contain dexpramipexole or apharmaceutically acceptable salt of dexpramipexole as the activeingredient. Alternatively, a pharmaceutical composition may containdexpramipexole or a pharmaceutically acceptable salt of dexpramipexoleas the active ingredient.

“Pharmaceutially acceptable salt” is meant to indicate those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of a patient without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al. (1977) J. Pharm.Sciences, Vol 6., 1-19, describes pharmaceutically acceptable salts indetail. A pharmaceutical acceptable “salt” is any acid addition salt,preferably a pharmaceutically acceptable acid addition salt, including,but not limited to, halogenic acid salts such as hydrobromic,hydrochloric, hydrofloric and hydroiodic acid salt; an inorganic acidsalt such as, for example, nitric, perchloric, sulfuric and phosphoricacid salt; an organic acid salt such as, for example, sulfonic acidsalts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic,benzenesulfonic or p-toluenesufonic, acetic, malic, fumaric, succinic,citric, benzonic gluconic, lactic, mandelic, mucic, pamoic, pantothenic,oxalic and maleic acid salts; and an amino acid salt such as aspartic orglutamic acid salt. The acid addition salt may be a mono- or di-acidaddition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric ordi-organic acid salt. In all cases, the acid addition salt is used as anachiral reagent which is not selected on the basis of any expected orknown preference for the interaction with or precipitation of a specificoptical isomer of the products of this disclosure.

As used herein, the term “daily dose amount” refers to the amount ofdexpramipexole per day that is administered or prescribed to a patient.This amount can be administered in multiple unit doses or in a singleunit does, in a single time during the day or at multiple times duringthe day.

A “dose amount” as used herein, is generally equal to the dosage of theactive ingredient which may be administered once per day, or may beadministered several times a day (e.g., the unit dose is a fraction ofthe desired daily dose). For example, a non-effective dose amount of 0.5mg/day of pramipexole may be administered as 1 dose of 0.5 mg, 2 dosesof 0.25 mg each or 4 doses of 0.125 mg. The term “unit dose” as usedherein may be taken to indicate a discrete amount of the therapeuticcomposition which comprises a predetermined amount of the activecompound in a single composition, or multiple compositions that areadministered at substantially the same time. A unit dose may representthe daily dose or may be a fraction of the daily dose.

Embodiments of the present invention relate to methods of treating acondition in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof, wherein the condition istreated. In some embodiments, the levels of plasma cells, B-cellprolymphocytes or a combination thereof in the subject is reducedfollowing administration to the subject of a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof.

Embodiments of the present invention relate to methods of treating acondition in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof, wherein the subject's level ofmyeloproliferative cells is reduced. In certain embodiments, themyeloproliferative cells are selected from plasma cells, B-cellprolymphocytes and a combination thereof.

Embodiments of the present invention relate to methods of treatingplasma cell disorders and B-cell disorders in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof,wherein the condition is treated. In some embodiments, the levels ofplasma cells, B-cells or a combination thereof in the subject is reducedfollowing administration to the subject of a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof.

Various embodiments described herein are directed to a method oftreating a condition characterized by normal levels of plasma cellsand/or B-cells or elevated levels of plasma cells and/or B-cells in asubject in need thereof comprising administering to the subject atherapeutically effective amount of dexpramipexole, or apharmaceutically acceptable salt thereof, wherein the levels of plasmacells and/or B-cells are reduced. In some embodiments, the condition ischaracterized by elevated levels of plasma cells and/or B-cells. In someembodiments, the condition is characterized by normal levels of plasmacells and/or B-cells in tissues including, but not limited to bonemarrow, bone, kidney, lymph nodes, and combinations thereof. In yetother embodiments, the condition is characterized by normal levels ofplasma cells and/or B-cells in the peripheral blood and tissues. In someembodiments, the condition is characterized by elevated levels of plasmacells and/or B-cells in tissues including, but not limited to bonemarrow, bone, kidney, lymph nodes, and combinations thereof. In yetother embodiments, the condition is characterized by elevated levels ofplasma cells and/or B-cell prolymphocytes in the peripheral blood andtissues. In some embodiments, the condition is multiple myeloma.

In some embodiments, the condition is characterized by normal levels ofplasma cells or elevated levels of plasma cells. In some embodiments,the condition is characterized by normal levels of B-cells or elevatedlevels of B-cells. In some embodiments, the condition is characterizedby elevated levels of B-cells with normal levels of plasma cells. Inother embodiments, the condition is characterized by elevated levels ofplasma cells with normal levels of B-cells. In other embodiments, thecondition is characterized by elevated levels of B-cells and elevatedlevels of plasma cells. In other embodiments, the condition ischaracterized by normal levels of B-cells and normal levels of plasmacells. In the foregoing embodiments, the normal or elevated levels ofplasma cells and/or B-cells (as the case may be) may be in tissuesincluding, but not limited to bone marrow, bone, kidney, lymph nodes,and combinations thereof. In the foregoing embodiments, the normal orelevated levels of plasma cells and/or B-cells (as the case may be) maybe in the peripheral blood and tissues.

In some embodiments, the condition is characterized by elevated levelsof plasma cells and/or B-cells in the peripheral blood, tissue, or acombination thereof. In some embodiments, the condition is characterizedby elevated levels of plasma cells and/or B-cells in tissue. In someembodiments, the condition is characterized by elevated levels of plasmacells and/or B-cells in tissues including, but not limited to bonemarrow, bone, kidney, lymph nodes, and combinations thereof. In yetother embodiments, the condition is characterized by elevated levels ofplasma cells and/or B-cells in the peripheral blood and tissues.

Some embodiments are directed to methods of treating a conditioncharacterized by elevated levels of plasma cells in a subject comprisingadministering to the subject in need thereof a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof,wherein the level of plasma cells are reduced. In some embodiments, thecondition is characterized by elevated levels of plasma cells in theperipheral blood, bone marrow, other tissues, or a combination thereof.In some embodiments, the condition is characterized by the presence ofmonoclonal proteins in peripheral blood, in urine or a combinationthereof.

In some embodiments, a condition characterized by elevated levels ofplasma cells is characterized by levels of plasma cells <10% of totalcells in the bone marrow and ≤3 grams per deciliter of serum monoclonalproteins. In some embodiments, a condition characterized by elevatedlevels of plasma cells is characterized by levels of plasma cells <10%of total cells in the bone marrow and serum β₂-microglobulin levels <3.5mg/liter. In some embodiments, a condition characterized by elevatedlevels of plasma cells is characterized by levels of plasma cells <10%of total cells in the bone marrow, serum β₂-microglobulin levels <3.5mg/liter and serum albumin levels ≥3.5 mg/deciliter. In otherembodiments, the condition is characterized by levels of plasma cells<10% of total cells in the bone marrow and serum β₂-microglobulin levels≥5.5 mg/liter. The condition may be further characterized by normalamounts of monoclonal proteins in the peripheral blood and variablesymptoms. In further embodiments, the condition is characterized bylevels of plasma cells <10% in the bone marrow and no serum monoclonalproteins present. In yet further embodiments, the condition may becharacterized by levels of plasma cells <10% of total cells in the bonemarrow, serum β₂-microglobulin levels from 3.5 mg/liter to <5.5mg/deciliter regardless of serum albumin levels. In other embodiments,the condition is characterized by levels of plasma cells <10% in thebone marrow and >2×10⁹ cells per liter or >20% of monoclonal proteins inthe peripheral blood and the presence of bone and/or kidney dysfunction.

In some embodiments, a condition characterized by elevated levels ofplasma cells is characterized by levels of plasma cells >10% of totalcells in the bone marrow and <3 grams per deciliter of serum monoclonalproteins. In other embodiments, the condition is characterized by levelsof plasma cells >10% of total cells in the bone marrow, serumβ₂-microglobulin levels <3.5 mg/liter, and serum albumin levels >3.5mg/deciliter. The condition may be further characterized by normal to aslight increase in amounts of monoclonal proteins in the peripheralblood. In addition, the condition may be classified as asymptomatic ormay have bone and/or kidney dysfunction. In further embodiments, thecondition is characterized by levels of plasma cells >10% of total cellsin the bone marrow, serum β₂-microglobulin levels <3.5 mg/liter, andserum albumin levels <3.5 mg/deciliter. The condition may be furthercharacterized by normal to a slight increase in amounts of monoclonalproteins in the peripheral blood and the presence of bone and/or kidneydysfunction. In yet further embodiments, the condition may becharacterized by levels of plasma cells >10% of total cells in the bonemarrow, serum β₂-microglobulin levels from 3.5 mg/liter to <5.5mg/deciliter regardless of serum albumin levels. The condition may befurther characterized by normal to a slight increase in amounts ofmonoclonal proteins in the peripheral blood and the presence of boneand/or kidney dysfunction. In other embodiments, the condition ischaracterized by levels of plasma cells >10% of total cells in the bonemarrow and serum β₂-microglobulin levels >5.5 mg/liter. The conditionmay be further characterized by normal to a slight increase in amountsof monoclonal proteins in the peripheral blood and the presence of boneand/or kidney dysfunction. In further embodiments, the condition ischaracterized by levels of plasma cells >10% in the bone marrow and noserum monoclonal proteins present.

In further embodiments, the condition is characterized by levels ofplasma cells >30% in the bone marrow and no serum monoclonal proteinspresent. The condition may be further characterized by normal to aslight increase in amounts of monoclonal proteins in the peripheralblood and the presence of bone and/or kidney dysfunction. In otherembodiments, the condition is characterized by levels of plasmacells >30% in the bone marrow and >2×10⁹ cells per liter or >20% ofmonoclonal proteins in the peripheral blood and the presence of boneand/or kidney dysfunction. In other embodiments, a conditioncharacterized by elevated levels of plasma cells is characterized bylevels of plasma cells >30% of total cells in the bone marrow and ≤3grams per deciliter of serum monoclonal proteins. In other embodiments,the condition is characterized by levels of plasma cells >30% of totalcells in the bone marrow, serum β₂-microglobulin levels <3.5 mg/liter,and serum albumin levels >3.5 mg/deciliter. The condition may be furthercharacterized by normal to a slight increase in amounts of monoclonalproteins in the peripheral blood. In addition, the condition may beclassified as asymptomatic or may have bone and/or kidney dysfunction.In further embodiments, the condition is characterized by levels ofplasma cells >30% of total cells in the bone marrow, serumβ₂-microglobulin levels <3.5 mg/liter, and serum albumin levels <3.5mg/deciliter. The condition may be further characterized by normal to aslight increase in amounts of monoclonal proteins in the peripheralblood and the presence of bone and/or kidney dysfunction. In yet furtherembodiments, the condition may be characterized by levels of plasmacells >30% of total cells in the bone marrow, serum β₂-microglobulinlevels from 3.5 mg/liter to <5.5 mg/deciliter regardless of serumalbumin levels. The condition may be further characterized by normal toa slight increase in amounts of monoclonal proteins in the peripheralblood and the presence of bone and/or kidney dysfunction. In otherembodiments, the condition is characterized by levels of plasmacells >30% of total cells in the bone marrow and serum β₂-microglobulinlevels ≥5.5 mg/liter. The condition may be further characterized bynormal to a slight increase in amounts of monoclonal proteins in theperipheral blood and the presence of bone and/or kidney dysfunction. Infurther embodiments, the condition is characterized by levels of plasmacells >30% in the bone marrow and no serum monoclonal proteins present.

In some embodiments, the condition is monoclonal gammopathy ofundetermined significance. Monoclonal gammopathy of undeterminedsignificance may be characterized by elevated levels of plasma cells ischaracterized by levels of plasma cells <10% of total cells in the bonemarrow and ≤3 grams per deciliter of serum monoclonal proteins.Monoclonal gammopathy of undetermined significance may be furthercharacterized by normal amounts of monoclonal proteins in the peripheralblood and variable symptoms.

In some embodiments, the condition is primary systemic amyloidosis.Primary systemic amyloidosis may be characterized by elevated levels ofplasma cells is characterized by levels of plasma cells <10% of totalcells in the bone marrow and ≤3 grams per deciliter of serum monoclonalproteins. Primary systemic amyloidosis may be further characterized bynormal amounts of monoclonal proteins in the peripheral blood andvariable symptoms.

In some embodiments, the condition is multiple myeloma. Multiple myelomamay be classified as stage I, stage II, or stage III. Stage I multiplemyeloma may be characterized by levels of plasma cells >10% of totalcells in the bone marrow, serum β₂-microglobulin levels <3.5 mg/liter,and serum albumin levels ≥3.5 mg/deciliter. Stage I multiple myeloma maybe further characterized by normal to a slight increase in amounts ofmonoclonal proteins in the peripheral blood. In addition, stage Imultiple myeloma may be may be further characterized by the presence ofbone and/or kidney dysfunction. Stage II multiple myeloma may becharacterized by levels of plasma cells >10% of total cells in the bonemarrow, serum β₂-microglobulin levels <3.5 mg/liter, and serum albuminlevels <3.5 mg/deciliter or serum β₂-microglobulin levels from 3.5mg/liter to <5.5 mg/deciliter regardless of serum albumin levels. StageII multiple myeloma may be further characterized by normal to a slightincrease in amounts of monoclonal proteins in the peripheral blood. Inaddition, stage II multiple myeloma may be further characterized by thepresence of bone and/or kidney dysfunction. Stage III multiple myelomamay be characterized by levels of plasma cells >10% of total cells inthe bone marrow, serum β₂-microglobulin levels ≥5.5 mg/liter. Stage IIImultiple myeloma may be further characterized by normal to a slightincrease in amounts of monoclonal proteins in the peripheral blood. Inaddition, stage III multiple myeloma may be further characterized by thepresence of bone and/or kidney dysfunction.

In some embodiments, the condition is smoldering myeloma. Smolderingmyeloma may be characterized by levels of plasma cells >10% of totalcells in the bone marrow, serum β₂-microglobulin levels <3.5 mg/liter,and serum albumin levels ≥3.5 mg/deciliter. Smoldering myeloma may befurther characterized by normal to a slight increase in amounts ofmonoclonal proteins in the peripheral blood. In addition, smolderingmyeloma may have bone and/or kidney dysfunction.

In some embodiments, the condition is nonsecretory myeloma. Nonsecretorymyeloma is characterized by levels of plasma cells above about 30% inthe bone marrow and no serum monoclonal proteins present. Nonsecretorymyeloma may be further characterized by normal to a slight increase inamounts of monoclonal proteins in the peripheral blood. In addition,nonsecretory myeloma may have the presence of bone and/or kidneydysfunction.

In some embodiments, the condition is a plasmacytoma.

In some embodiments, the condition is plasma cell leukemia. Plasma cellleukemia may be characterized by levels of plasma cells >10% in the bonemarrow. Plasma cell leukemia may be further characterized by >2×10⁹cells per liter or >20% of monoclonal proteins in the peripheral blood.In addition, plasma cell leukemia may have the presence of bone and/orkidney dysfunction.

Some embodiments are directed to methods of treating a conditioncharacterized by elevated levels of B-cells in a subject comprisingadministering to the subject in need thereof a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof,wherein the level of B-cells are reduced. In some embodiments, thecondition is characterized by elevated levels of B-cell prolymphocytesin the peripheral blood, bone marrow, other tissues, or a combinationthereof. In some embodiments, a condition characterized by elevatedlevels of B-cells is characterized by an increased percentage of B-cellprolymphocytes above about 55% in the peripheral blood. In someembodiments, a condition characterized by elevated levels of B-cells ischaracterized by an increased percentage of B-cell prolymphocytes aboveabout 55% in the bone marrow.

In some embodiments, the condition is selected from diffuse large B-celllymphoma, follicular lymphoma, marginal zone lymphoma (MZL), small celllymphocytic lymphoma, mantle cell lymphoma (MCL), Burkitt lymphoma,Waldenström's macroblobulinemia, or any combination thereof.

In other embodiments, the condition is a B-cell leukemia selected fromB-cell chronic lymphocytic leukemia, B-cell acute lymphoblasticleukemia, B-cell acute lymphocytic leukemia, B-cell prolymphocyticleukemia, precursor B-cell lymphoblastic leukemia, hairy cell leukemia,or any combination thereof.

In some embodiments, the condition is B-cell prolymphocytic leukemia.

In some embodiments, treating the condition results in a reduction ofthe levels of plasma cells and/or B-cells. In some embodiments, thereduction of the levels of plasma cells and/or B-cells is in theperipheral blood, tissue, or a combination thereof. In certainembodiments, treating the condition results in a reduction of the levelsof plasma cells and/or B-cells in tissues including, but not limited tobone marrow, bone, kidney, lymph nodes, and combinations thereof. Incertain embodiments, the levels are reduced by at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95%, or 100%. In certain embodiments, the levels arereduced to normal. In certain embodiments, the levels are reduced tozero within the level of detection.

In some embodiments, a subject with normal levels of plasma cells is asubject with levels of plasma cells considered to be within the normalrange or limits for the particular subject and/or condition. In someembodiments, a subject with normal levels of plasma cells ischaracterized by levels of plasma cells less than about 10% of totalcells in the bone marrow. In some embodiments, a subject with elevatedlevels of plasma cells is a subject with levels of plasma cellsconsidered to be outside of the normal range or limit for the particularsubject and/or condition. In some embodiments, the condition ischaracterized by levels of plasma cells above about 10% of total cellsin the bone marrow. In some embodiments, the condition is characterizedby levels of plasma cells above about 30% of total cells in the bonemarrow.

In some embodiments, a subject with normal levels of plasma cells is asubject with levels of plasma cells considered to be within the normalrange or limits for the particular subject and/or condition. In someembodiments, the condition is characterized by the presence ofmonoclonal proteins in the serum, in the urine or a combination thereof.In some embodiments, the condition is characterized by serum monoclonalimmunoglobulin levels of ≤3 grams/deciliter. In some embodiments, asubject with elevated levels of plasma cells is a subject with levels ofplasma cells considered to be outside of the normal range or limit forthe particular subject and/or condition. In some embodiments, thecondition is characterized by the presence of monoclonal proteins in theblood, in the urine or a combination thereof. In some embodiments, thecondition is characterized by serum monoclonal immunoglobulin levels of≥3 grams/deciliter. In some embodiments, the condition is characterizedby serum β₂-microglobulin levels <3.5 mg/liter and serum albumin levels≥3.5 g/deciliter. In some embodiments, the condition is characterized byserum β₂-microglobulin levels <3.5 mg/liter and serum albumin levels<3.5 mg/deciliter, or serum β₂-microglobulin levels from 3.5 mg/liter to<5.5 mg/liter regardless of serum albumin level. In some embodiments,the condition is characterized by serum β₂-microglobulin levels ≥5.5mg/liter.

In some embodiments, a subject with normal levels of plasma cells is asubject with levels of plasma cells considered to be within the normalrange or limits for the particular subject and/or condition. In someembodiments, a subject with normal levels of plasma cells ischaracterized by levels of plasma cells of less than about 1% of cellsin the peripheral blood. In some embodiments, a subject with normallevels of plasma cells is characterized by levels of plasma cells ofless than about 3% of cells in the peripheral blood. In someembodiments, a subject with elevated levels of plasma cells is a subjectwith levels of plasma cells considered to be outside of the normal rangeor limit for the particular subject and/or condition. In someembodiments, a condition characterized by elevated levels of plasmacells is characterized by levels of plasma cells above about 3% of cellsin the peripheral blood. In some embodiments, a condition characterizedby elevated levels of plasma cells is characterized by levels of plasmacells selected from above about 5% of cells in the peripheral blood,about 10% of cells in the peripheral blood, and about 20% of cells inthe peripheral blood. In some embodiments, a condition characterized byelevated levels of plasma cells is characterized by levels of plasmacells above about 0.5×10⁹ cells per liter in the peripheral blood. Inyet other embodiments a condition characterized by elevated levels ofplasma cells is characterized by levels of plasma cells selected fromabove about 1.0×10⁹ cells per liter in the peripheral blood, about1.5×10⁹ cells per liter in the peripheral blood, about 2.0×10⁹ cells perliter in the peripheral blood.

In some embodiments, a subject with elevated levels of B-cells is asubject with levels of B-cells considered to be outside of the normalrange or limit for the particular subject and/or condition. In someembodiments, a condition characterized by elevated levels of B-cells ischaracterized by levels of B-cell prolymphocytes above about 15% in theperipheral blood. In some embodiments, a condition characterized byelevated levels of B-cells is characterized by an increased percentageof B-cell prolymphocytes selected from above about 55% in the peripheralblood, about 75% in the peripheral blood, and about 90% in theperipheral blood.

In some embodiments, a subject with elevated levels of B-cells is asubject with levels of B-cells considered to be outside of the normalrange or limit for the particular subject and/or condition. In someembodiments, a condition characterized by elevated levels of B-cells ischaracterized by levels of B-cell prolymphocytes above about 15% in thebone marrow. In some embodiments, a condition characterized by elevatedlevels of B-cell is characterized by an increased percentage of B-cellprolymphocytes selected from above about 55% in the bone marrow, about75% in the bone marrow, and about 90% in the bone marrow.

In some embodiments, the condition is selected from B-celllymphocytosis, chronic lymphocytic leukemia, and diffuse large B-celllymphoma.

In some embodiments, the condition is not a neurodegenerative disease.In some embodiments, the condition is not Parkinson's disease,Alzheimer's disease, or amyotrophic lateral sclerosis.

In some embodiments, administering a therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof may includeadministering daily doses of about 0.1 mg or more, about 1 mg or more,about 10 mg or more, about 50 mg or more, about 75 mg or more, about 100mg or more, about 125 mg or more, about 150 mg or more, about 175 mg ormore, about 200 mg or more, about 225 mg or more, about 250 mg or more,about 275 mg or more, about 300 mg or more, about 400 mg or more, about450 mg or more, about 500 mg or more, about 600 mg or more, about 700 mgor more, about 800 mg or more or about 1,000 mg or more, about 1,200 mgor more or about 1,500 mg or more.

In some embodiments, the therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 50 mg to about 1,500 mg per day. In some embodiments, thetherapeutically effective amount is from about 100 mg to about 1,500 mgper day. In some embodiments, the therapeutically effective amount isfrom about 150 mg to about 1,500 mg per day. In some embodiments, thetherapeutically effective amount is from about 300 mg to about 1,500 mgper day. In some embodiments, the therapeutically effective amount isfrom about 50 mg to about 300 mg per day. In some embodiments, thetherapeutically effective amount is from about 150 mg to about 300 mgper day.

In some embodiments, administering a therapeutically effective amountcomprises administering the daily dose as a fraction of the daily dose(as described herein) two or more times per day. In some embodiments,administering a therapeutically effective amount comprises administeringa dose equal to about half of a daily dose twice per day. In someembodiments, the dose is administered every about 12 hours. In someembodiments, administering a therapeutically effective amount comprisesadministering about 75 mg two times per day. In some embodiments,administering a therapeutically effective amount comprises administeringabout 25 mg two times per day, about 75 mg two times per day, about 150mg two times per day, or about 300 mg two times per day.

In some embodiments, administering a therapeutically effective amountcomprises administering a single unit dose of dexpramipexole of about0.1 mg or more, about 1 mg or more, about 10 mg or more, about 25 mg ormore, about 50 mg or more, about 75 mg or more, about 100 mg or more,about 125 mg or more, about 150 mg or more, about 175 mg or more, about200 mg or more, about 225 mg or more, about 250 mg or more, about 275 mgor more, about 300 mg or more, about 400 mg or more, about 450 mg ormore, about 500 mg or more, about 600 mg or more, about 700 mg or more,about 800 mg or more, about 1,000 mg or more, about 3,000 mg or more, orabout 5,000 mg or more. In some embodiments, the single unit dosecomprises from about 600 mg to about 900 mg of dexpramipexole.

In some embodiments, administering a therapeutically effective amountcomprises administering a single unit dose amount of dexpramipexole or apharmaceutically acceptable salt thereof from about 25 mg to about 5,000mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000mg, from about 150 mg to about 5,000 mg, from about 200 mg to about5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg toabout 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg toabout 5,000 mg, from about 100 mg to about 3,000 mg, from about 150 mgto about 3,000 mg, from about 200 mg to about 3,000 mg, from about 250mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100mg to about 1,000 mg, from about 150 mg to about 1,000 mg, from about200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, fromabout 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg,from 450 mg to about 1,000 mg, from about 500 mg to about 1000 mg, fromabout 600 mg to about 1,000 mg. In some embodiments, the single unitdose amount may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/dayto 600 mg/day. In some embodiments, the single unit dose amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 600 mg to about 900 mg. In some embodiments, the single unit doseamount of dexpramipexole or a pharmaceutically acceptable salt thereofis from about 300 mg to about 1,500 mg. In some embodiments, such singleunit doses may be administered once per day or multiple times per day,such as twice per day or three times per day.

In another embodiment, administering a therapeutically effective amountcomprises administering a single unit dose comprising at least about 50mg of dexpramipexole or a pharmaceutically acceptable salt thereof andno more than about 1.5 mg of pramipexole. In another aspect, the presentinvention provides a single unit dose comprising at least about 75 mg ofdexpramipexole or a pharmaceutically acceptable salt thereof and no morethan about 1.5 mg of pramipexole, or at least about 100 mg ofdexpramipexole or a pharmaceutically acceptable salt thereof and no morethan about 1.5 mg of pramipexole. In some embodiments, the single unitdose comprises no more than 1.0 mg, no more than 0.333 mg no more than0.3 mg no more than 0.2 mg, no more than 0.125 mg of pramipexole.

In some embodiments, the single unit dose further comprises apharmaceutically acceptable carrier. In some embodiments, such singleunit doses may be administered once per day or multiple times per day,such as twice per day or three times per day.

One of ordinary skill in the art will understand and appreciate thedosages and timing of the dosages to be administered to a subject inneed thereof. The doses and duration of treatment may vary, and may bebased on assessment by one of ordinary skill in the art based onmonitoring and measuring improvements in neuronal and non-neuronaltissues. This assessment may be made based on outward physical signs ofimprovement, such as increased muscle control, or on internalphysiological signs or markers. The doses may also depend on thecondition or disease being treated, the degree of the condition ordisease being treated and further on the age, weight, body mass indexand body surface area of the subject.

In some embodiments, therapeutically effective amounts, daily doses, orsingle unit doses of dexpramipexole may be administered once per day ormultiple times per day, such as 1 to 5 doses, twice per day or threetimes per day.

Embodiments are also directed to a dosage regimen for administeringdexpramipexole or a pharmaceutically acceptable salt thereof to treatthe conditions disclosed herein. For example, in some embodiments, themethods described herein may comprise a dosage regimen that may includea plurality of daily doses having an equal amount of dexpramipexole or apharmaceutically acceptable salt thereof as the initial dose in one ormore unit doses. In other embodiments, the dosage regimen may include aninitial dose of dexpramipexole or a pharmaceutically acceptable saltthereof in one or more unit doses, then a plurality of daily doseshaving a lower amount of dexpramipexole or a pharmaceutically acceptablesalt thereof as the initial dose in one or more unit doses. The dosageregimen may administer an initial dose followed by one or moremaintenance doses. The plurality of doses following the administering ofan initial dose may be maintenance doses.

Such embodiments are not limited by the amount of the initial dose anddaily doses. For example, in particular embodiments, the initial doseand each of the plurality of daily doses may be from about 0.1 mg ormore, about 1 mg or more, about 10 mg or more, about 50 mg or more,about 75 mg or more, about 100 mg or more, about 125 mg or more, about150 mg or more, about 175 mg or more, about 200 mg or more, about 225 mgor more, about 250 mg or more, about 275 mg or more, about 300 mg ormore, about 400 mg or more, about 450 mg or more, about 500 mg or more,about 600 mg or more, about 700 mg or more, about 800 mg or more, about1,000 mg or more, 1,200 mg or more, or about 1,500 mg or more ofdexpramipexole. In some embodiments, the one or more unit doses of thedosage regimen may be 1 to 5 unit doses, and in such embodiments, eachof the one or more unit doses may be substantially equal.

In some embodiments, two unit doses of about 75 mg are administereddaily, wherein each unit dose may be substantially equal. In someembodiments, three unit doses of about 75 mg are administered daily,wherein each unit dose may be substantially equal.

In other embodiments, the maintenance therapy dosing may includeadministering less than the initial daily dose, such as less than about50 mg, less than about 75 mg, less than about 150 mg, less than about300 mg, or less than 600 mg of dexpramipexole per day. Following theinitial dosing regimen, the subject may be administered a maintenancedosing regimen of, for example, about 0.1 mg or more, about 1 mg ormore, about 10 mg or more, about 50 mg or more, about 75 mg or more,about 100 mg or more, about 125 mg or more, about 150 mg or more, about175 mg or more, about 200 mg or more, about 225 mg or more, about 250 mgor more, about 275 mg or more, about 300 mg or more, about 400 mg ormore, about 450 mg or more, about 500 mg or more, about 600 mg or more,about 700 mg or more, about 800 mg or more, or about 1,000 mg or more,about 1,200 mg or more, or about 1,500 mg or more of dexpramipexole fora period of time such as, for example, at least 12 weeks or more or atleast 6 months or 1, 2, 3, 5 or 10 years or more.

In further embodiments, the method may include an initial dosing regimenand a maintenance dosing regimen. In certain embodiments, the initialdosing regimen may include administering a higher dose of dexpramipexoleor a pharmaceutically acceptable salt thereof than the maintenancedosing regimen as either a single administration or by administering anincreased dosage for a limited period of time prior to beginning amaintenance dosing regimen of dexpramipexole or a pharmaceuticallyacceptable salt thereof. In some embodiments, subjects undergoing amaintenance regimen may be administered one or more higher-dosagetreatments at one or more times during the maintenance dosage regimen.

In certain embodiments, the initial dosing regimen and the maintenancedosing regimen may be about 50 mg to about 1500 mg or more ofdexpramipexole, about 150 mg to about 300 mg or more of dexpramipexole,about 300 mg to about 500 mg or more of dexpramipexole per day, or fromabout 300 mg to about 600 mg or more of dexpramipexole per day.

In some embodiments, the initial dosing regimen and the maintenancedosing regimen may include administering dexpramipexole or apharmaceutically acceptable salt thereof once per day, multiple timesper day, such as twice per day or three times per day. In suchembodiments, the dosage regimen may continue administering an initialdose for 1, 2, 3, 4, 5, 6 or 7 days, up to 4 weeks, up to 8 weeks or upto 12 weeks. In some embodiments, the dosage regimen for administeringan initial dose and/or a maintenance dose may continue for an extendedperiod of time. Various embodiments are directed to a dosing regimen fordexpramipexole or a pharmaceutically acceptable salt thereof in whichmaintenance doses are maintained for an extended period of time withouttitration or otherwise changing the dosing regimen. In such embodiments,the extended period of time may be about 12 weeks or longer, about 6months or longer, about 1 year or longer, 2, 3, 4, 5, or 10 years orlonger, and in certain embodiments, an indefinite period of time.

Each of the dosage regimens for dexpramipexole described herein may beused in any of the methods, and the dosing regimen may be carried outusing any of the compositions described herein.

In some embodiments, treatment with a therapeutically effective amountof dexpramipexole is without the adverse side effects associated withdopamine agonism.

Some embodiments further comprise administering to the subject atherapeutically effective amount of one or more secondary agents. Insome embodiments, the therapeutically effective amount of dexpramipexoleor salt thereof and the therapeutically effective amount of the one ormore secondary agents may be administered individually or combined intoa single dosage composition. In some embodiments, the therapeuticallyeffective amount of dexpramipexole or salt thereof and thetherapeutically effective amount of the one or more secondary agents areadministered simultaneously or sequentially.

In some embodiments, the one or more secondary agent is any drug thatinduces anti-inflammatory effects or is capable of decreasing levels ofplasma cells and/or B-cells in the subject. In some embodiments, thesecondary agent is an antibody. In some embodiments, the secondary agentis not dexpramipexole. In some embodiments, the secondary agent isselected from a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), an intravenous immunoglobulin, a tyrosine kinase inhibitor, afusion protein, a monoclonal antibody directed against one or morepro-inflammatory cytokines, a chemotherapeutic agent and a combinationthereof. In some embodiments, the secondary agent may be aglucocorticoid, a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), a phenolic antioxidant, an anti-proliferative drug, a tyrosinekinase inhibitor, an anti IL-5 or an IL5 receptor monoclonal antibody,an anti IL-13 or an anti IL-13 receptor monoclonal antibody, an IL-4 oran IL-4 receptor monoclonal antibody, an anti IgE monoclonal antibody, amonoclonal antibody directed against one or more pro-inflammatorycytokines, a TNF-α inhibitor, a fusion protein, a chemotherapeutic agentor a combination thereof. In some embodiments, the secondary agent is ananti-inflammatory drug. In some embodiments, anti-inflammatory drugsinclude, but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, curcumin, deflazacort, desonide, desoximetasone,dexamethasone dipropionate, diclofenac potassium, diclofenac sodium,diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate,diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab,enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole,fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac,flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate,flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate, lysofylline,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, mepolizumab, prodrugsthereof, and a combination thereof. In some embodiments the tyrosinekinase inhibitor is imatinib. In some embodiments the anti IL-5monoclonal antibody is mepolizumab or reslizumab. In some embodiments,the IL-5 receptor monoclonal antibody is benralizumab. In someembodiments, the anti IL-13 monoclonal antibody is lebrikizumab ordulipumab. In some embodiments the anti IL-4 monoclonal antibody isdulipumab. In some embodiments, the anti IgE monoclonal antibody isomalizumab. In some embodiments, the TNF-α inhibitor is infliximab,adalimumab, certolizumab pegol, or golimumab. In some embodiments, thefusion protein is etanercept.

Some embodiments further comprise administering to the subject atherapeutically effective procedure such as plasmapheresis.

Various embodiments may also comprise an induction step comprisingadministration of a therapeutically effective amount of a secondaryagent that induces anti-inflammatory effects or is capable of decreasinglevels of plasma cells and/or B-cells in the subject prior toadministration of a therapeutically effective amount of dexpramipexoleor a pharmaceutically acceptable salt thereof. In some embodiments,administration of the secondary agent may continue or may becomediscontinued once administration of dexpramipexole or pharmaceuticallyacceptable salt thereof starts.

In some embodiments, the induction step comprises administering atherapeutically effective amount of the secondary agent for a period ofabout 1 day to about 6 months. In some embodiments, the secondary agentis administered for a period of about 1 day, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks,about 3 weeks, about 1 month, about 2 months, about 3 months, about 4months, about 5 months, or about 6 months. In some embodiments, theinduction step comprises administering a therapeutically effectiveamount of the secondary agent for a period of less than 1 week, about 1to 2 weeks, about 2 to 3 weeks, about 3 to 4 weeks, about 1 to 2 months,about 2 to 3 months, or about 3 to 4 months. In yet other embodiments,the induction step comprises administering a therapeutically effectiveamount of the secondary agent until a pre-determined level of plasmacells and/or B-cells is reached, after which the induction step isdiscontinued, titrated out, or a combination thereof. In someembodiments, the induction step may use any of the methods describedherein. In some embodiments, the induction step is followed by theadministration of the dosage regimens for dexpramipexole describedherein as well as any of the compositions described herein.

In any of the embodiments described, a therapeutically effective amountof dexpramipexole or a pharmaceutically acceptable salt thereof and atherapeutically effective amount of one or more of the secondary agentsdescribed above may be provided adjunctively in separate pharmaceuticalcompositions or in a single dose pharmaceutical composition in which thedexpramipexole or a pharmaceutically acceptable salt thereof and one ormore secondary agent are combined. In some embodiments, the one or moresecondary agent is a therapeutic agent capable of decreasing levels ofplasma cells and/or B-cells in the subject.

Specific modes of administration of dexpramipexole or salt thereof willdepend on the indication. The selection of the specific route ofadministration and the dose regimen may be adjusted or titrated by theclinician according to methods known to the clinician in order to obtainthe optimal clinical response. The amount of compound to be administeredmay be that amount which is therapeutically effective. The dosage to beadministered may depend on the characteristics of the subject beingtreated, e.g., the particular animal or human subject treated, age,weight, body mass index, body surface area, health, types of concurrenttreatment, if any, and frequency of treatments, and can be easilydetermined by one of skill in the art (e.g., by the clinician).

In the embodiments described herein, the therapeutically effectiveamount of dexpramipexole or pharmaceutically acceptable salt thereof maybe administered in a pharmaceutical composition. Each of thepharmaceutical compositions described herein may be used in any of themethods or dosage regimens described herein.

In some embodiments, administering a therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof may includeadministering dexpramipexole or a pharmaceutically acceptable saltthereof in a controlled release form.

Pharmaceutical compositions containing dexpramipexole or apharmaceutically acceptable salt thereof in a solid dosage may include,but are not limited to, softgels, tablets, capsules, cachets, pellets,pills, powders and granules; topical dosage forms which include, but arenot limited to, solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels and jellies, and foams; andparenteral dosage forms which include, but are not limited to,solutions, suspensions, emulsions, and dry powder; comprising aneffective amount of a polymer or copolymer of the present invention.

It is also known in the art that the active ingredients may be containedin such compositions with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) can be consulted.

In some embodiments, pharmaceutical compositions may be suitable fororal administration such as, for example, a solid oral dosage form or acapsule, and in certain embodiments, the composition may be a tablet.Such tablets may include any number of additional agents such as, forexample, one or more binder, one or more lubricant, one or more diluent,one or more surface active agent, one or more dispersing agent, one ormore colorant, and the like. Such tablets may be prepared by any methodknown in the art, for example, by compression or molding. Compressedtablets may be prepared by compressing in a suitable machine theingredients of the composition in a free-flowing form such as a powderor granules, and molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets, of some embodiments, may be uncoated and,in other embodiments, they may be coated by known techniques.

In other embodiments, the pharmaceutical compositions may be provided ina dragee core with suitable coatings. In such embodiments, dragee coresmay be prepared using concentrated sugar solutions, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. In some embodiments,dyestuffs or pigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses. In yet other embodiments, pharmaceutical compositionsincluding a therapeutically effective amount of dexpramipexole preparedfor oral administration may include, but are not limited to, push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as, e.g., lactose, binders such as, e.g., starches, and/orlubricants such as, e.g., talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added. Allcompositions for oral administration should be in dosages suitable forsuch administration.

In embodiments in which the tablets and dragee cores are coated, thecoatings may delay disintegration and absorption in the gastrointestinaltract and thereby providing a sustained action over a longer period.Additionally, such coatings may be adapted for release of dexpramipexoleor a pharmaceutically acceptable salt thereof in a predetermined pattern(e.g., in order to achieve a controlled release composition) or it maybe adapted not to release the active compound until after passage of thestomach (enteric coating). Suitable coatings encompassed by suchembodiments may include, but are not limited to, sugar coating, filmcoating (e.g., hydroxypropyl methylcellulose, methylcellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose,acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone),or an enteric coating (e.g., methacrylic acid copolymer, celluloseacetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac,and/or ethyl cellulose). Furthermore, a time delay material such as, forexample, glyceryl monostearate or glyceryl distearate may beincorporated into the coatings of some embodiments. In still otherembodiments, solid tablet compositions may include a coating adapted toprotect the composition from unwanted chemical changes, for example, toreduce chemical degradation prior to the release of the active drugsubstance.

In some embodiments, the pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beprepared as suspensions, solutions or emulsions in oily or aqueousvehicles suitable for injection. In such embodiments, such liquidcompositions may further include formulatory agents such as suspending,stabilizing and or dispersing agents formulated for parenteraladministration. Such injectable compositions may be administered by anyroute, for example, subcutaneous, intravenous, intramuscular,intra-arterial or bolus injection or continuous infusion, and inembodiments in which injectable compositions are administered bycontinuous infusion, such infusion may be carried out for a period ofabout 15 minutes to about hours. In certain embodiments, compositionsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative.

In other embodiments, dexpramipexole may be formulated as a depotpreparation, and such long acting compositions may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Depot injections may be administered at about 1to about 6 months or longer intervals. In some embodiments, thefrequency of doses of the dexpramipexole described herein administeredby depot injection may be once a month, every three months, or once ayear. The compounds may be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In still other embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated for buccal or sublingual administration. In such embodiments,the pharmaceutical compositions may be prepared as chewable tablets,flash melts or lozenges formulated in any conventional manner.

In yet other embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated for administration by inhalation. In such embodiments,pharmaceutical compositions may be delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

In further embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beadministered intranasally or by inhalation including, but not limitedto, an intranasal spray or by pulmonary inhalation with an appropriatecarrier. One suitable route of administration is a depot form formulatedfrom a biodegradable suitable polymer, e.g.,poly-D,L-lactide-coglycolide as microcapsules, microgranules orcylindrical implants containing dispersed dexpramipexole.

In further embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated in rectal compositions such as suppositories or retentionenemas, e.g., containing conventional suppository bases such as cocoabutter or other glycerides.

In some embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated for transdermal administration. For example, suchpharmaceutical compositions may be prepared to be applied to a plasteror applied by transdermal, therapeutic systems supplied to the subject.In other embodiments, pharmaceutical and therapeutic compositionsincluding dexpramipexole or a pharmaceutically acceptable salt thereoffor transdermal administration may include a suitable solid or gel phasecarriers or excipients such as, but are not limited to, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as, e.g., polyethyleneglycols.In some embodiments, pharmaceutical compositions includingdexpramipexole may be administered alone as a single therapeutic agent.In other embodiments, the pharmaceutical compositions includingdexpramipexole may be administered in combination with one or more otheractive ingredients, such as, for example, adjuvants, proteaseinhibitors, or other compatible drugs or compounds where such acombination is seen to be desirable or advantageous in achieving thedesired effects of the methods described herein.

The pharmaceutical compositions described herein may be prepared,packaged, or sold in bulk as a single unit dose or as multiple unitdoses and may be administered in the conventional manner by any routewhere they are active. For example, the compositions may be administeredorally, ophthalmically, intravenously, intramuscularly,intra-arterially, intramedullary, intrathecally, intraventricularly,transdermally, subcutaneously, intraperitoneally, intravesicularly,intranasally, enterally, topically, sublingually, rectally, byinhalation, by depot injections, or by implants or by use of vaginalcreams, suppositories, pessaries, vaginal rings, rectal suppositories,intrauterine devices, and transdermal forms such as patches and creams.Specific modes of administration will depend on the indication. Theselection of the specific route of administration and the dose regimenmay be adjusted or titrated by the clinician according to known methodsin order to obtain the optimal clinical response. All of the methodsdescribed herein may be carried out by administering dexpramipexole byany such route for administration described herein. Additionally,dexpramipexole may be delivered by using any such route ofadministration for all of the dosage regimens described herein. Thecompositions and amounts of non-active ingredients in such a compositionmay depend on the amount of the active ingredient, and on the size andshape of the tablet or capsule. Such parameters may be readilyappreciated and understood by one of skill in the art.

In some embodiments, the pharmaceutical compounds may be formulatedreadily by combining these compounds with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a subject tobe treated. Pharmaceutical preparations for oral use may be obtained byadding a solid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, but are not limited to, fillers such as sugars, including, butnot limited to, lactose, sucrose, mannitol, and sorbitol; cellulosepreparations such as, but not limited to, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). In some embodiments, disintegrating agentsmay be added, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

In some embodiments, the pharmaceutical composition may include adiluent in an amount from about 20% to about 50% by weight of saidcomposition; optionally, a second diluent in an amount from about 10% toabout 30% by weight of said composition; optionally, a disintegrant inan amount from about 2% to about 6% of said composition; optionally, alubricant in an amount from about 0.01% to about 2% of said composition;and dexpramipexole. In further embodiments, the pharmaceuticalcomposition may include any amount or combination of microcrystallinecellulose, mannitol, croscarmellose sodium, crospovidone, croscarmellosemagnesium stearate, or combination thereof. In some embodiments, thepharmaceutical composition may include microcrystalline cellulose,mannitol, croscarmellose sodium, magnesium stearate, or a combinationthereof. In other embodiments, the pharmaceutical composition mayinclude microcrystalline cellulose in an amount from about 20% to about50% by weight of said composition; mannitol in an amount from about 10%to about 30% by weight of said composition; crospovidone in an amountfrom about 2% to about 6% of said composition; magnesium stearate in anamount from about 0.01% to about 2% of said composition; anddexpramipexole.

The pharmaceutical composition may have a chiral purity fordexpramipexole of at least 99.5%, preferably at least 99.6%, preferablyat least 99.7%, preferably at least 99.8%, preferably at least 99.9%,preferably at least 99.95%, or more preferably at least 99.99%. In someembodiments, the chiral purity for dexpramipexole is 100%. In someembodiments, the composition has a chiral purity for dexpramipexole of99.9% or greater. In some embodiments, the composition has a chiralpurity for dexpramipexole of 99.95% or greater. In some embodiments, thecomposition has a chiral purity for dexpramipexole of 99.99% or greater.The high chiral purity of the pramipexole used herein, dexpramipexole,allows for therapeutic compositions that may have a wide individual anddaily dose range.

The embodiments for amounts of dexpramipexole or a pharmaceuticallyacceptable salt thereof in the pharmaceutical composition, chiralpurity, and dosage form, which are described herein separately for thesake of brevity, may be joined in any suitable combination.

In a further embodiment, a pharmaceutical composition may comprise atherapeutically effective amount of dexpramipexole or a pharmaceuticallyacceptable salt thereof and a NOAEL dose amount of pramipexole. Thepharmaceutical composition may further comprise a pharmaceuticallyacceptable carrier and/or excipient. Such embodiments may furtherinclude one or more diluent, one or more disintegrant, one or morelubricant, one or more pigment or colorant, one or more gelatin, one ormore plasticizer and the like.

In some embodiments, the NOAEL dose amount of pramipexole is less thanabout 1.50 mg. In other embodiments, the NOAEL dose amount ofpramipexole is an amount that does not exceed about 1.0 mg. In certainembodiments, the NOAEL dose amount of pramipexole is an amount that doesnot exceed about 0.75 mg, about 0.5 mg, about 0.25 mg, about 0.125 mg orabout 0.05 mg. In some embodiments, the NOAEL dose amount of pramipexoleis less than about 0.5 mg, less than about 0.125 mg, or less than about0.05 mg. In some embodiments, the therapeutically effective amount ofdexpramipexole and a NOAEL amount of pramipexole are administered in asingle unit dose form.

Embodiments of the invention are not limited to any particular agentencompassed by the classes of agents described above, and any agent thatfalls within any of these categories may be utilized in embodiments ofthe invention. Non-limiting examples of such agents are provided forclarity. Any of the secondary agents described above may be useful inembodiments of the invention.

The embodiments for disease states, subject type, daily dose amounts,therapeutically effective amounts, no observable adverse effect leveldose amounts, non-effective dose amounts, pharmaceutical compositions,and chiral purities for the methods of the invention, which aredescribed herein separately for the sake of brevity, can be joined inany suitable combination.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using “consisting of” or “consisting essentially of” language,rather than “comprising”. When used in the claims, whether as filed oradded per amendment, the transition term “consisting of” excludes anyelement, step, or ingredient not specified in the claims. The transitionterm “consisting essentially of” limits the scope of a claim to thespecified materials or steps and those that do not materially affect thebasic and novel characteristic(s). Embodiments of the invention soclaimed are inherently or expressly described and enabled herein.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

Example 1

Effects of Dexpramipexole on Minipig Eosinophils

In a 39-week repeat-dose toxicology study, minipigs were dosed at 0,7.5, 25, and 75 mg/kg dexpramipexole by daily oral gavage through StudyDay 45 and at 0, 7.5, 25, and 50 mg/kg dexpramipexole from Study Day 46to study completion. As shown in FIG. 1, dexpramipexole produced both adose- and time-dependent reduction in eosinophils. The effects ofdexpramipexole treatment on minipig eosinophils was statisticallysignificant at 39 weeks in the 25 mg/kg group and at all time points inthe 50/75 mg/kg group. These differences were not considered adversefrom a safety perspective.

Example 2

Eosinophil and Basophil Reductions in a Phase 2 Trial in ALS Subjects

In a Phase 2 trial in ALS, a dose- and time-dependent decrease ineosinophil counts was seen among subjects receiving dexpramipexoletreatment. The Phase 2 trial was a two-part, double-blind study thatevaluated the safety, tolerability, and clinical effects ofdexpramipexole in ALS patients.

In Part 1, subjects were randomized to placebo (n=27), 50 mg/day (n=23),150 mg/day (n=26), or 300 mg/day dexpramipexole (n=26) for 12 weeks.From baseline to week 12, mean serum eosinophils increased by 29.2% inthe placebo group and declined by 18.2% (p=0.0370), 69.9%, (p<0.0001),and 42.9% (p=0.0008) in the 50 mg, 150 mg, and 300 mg groups,respectively (FIG. 2A).

During a one-month washout following week 12, mean eosinophils at week16 recovered to 47% and 73% of baseline levels in the 150 and 300 mg/daygroups, respectively.

Following drug washout, subjects in part 2 re-randomized to 150 mg twicedaily had a greater decline in eosinophils from week 16 to week 40 thansubjects re-randomized to 25 mg twice daily (78.9% vs 17.6%, p=0.011).

Example 3

Eosinophil-Lowering and Basophil-Lowering Effects of Dexpramipexole in aPhase 3 Trial

The phase 3 clinical trial was a double-blind study of dexpramipexole inALS patients randomized 1:1 to placebo or dexpramipexole 300 mg dailytreatment. Hematology parameters were collected as part of routinesafety monitoring. Eosinophil and basophil counts were retrospectivelyanalyzed by visit.

Eosinophil levels were summarized over available time points andanalyzed by ANOVA testing the effect of treatment vs. placebo on meanchanges in serum eosinophil counts from baseline. Subjects with baselineeosinophils from 0 to 0.02×10⁹/L (constituting less than 2% of allsubjects analyzed) were censored from the primary analysis because ofthe inherent limitation to observe a decline from baseline.

The eosinophil-lowering effect developed slowly, reached plateau atabout month 4, and persisted through month 12 (FIG. 2B). A profounddecrease in peripheral blood eosinophil count was observed after 8-12weeks of treatment with dexpramipexole that persisted for the durationof the trial. Statistical analysis of the change from baseline wasperformed at month 6 to remove the effect of study dropouts in latermonths. At this time point, mean eosinophil counts were 68.4% reducedfrom baseline (p<0.0001).

The effect of dexpramipexole in reducing eosinophil counts was observedin most patients, with 77.5% of dexpramipexole-treated subjectsexperiencing a 50% or greater decline in eosinophil count after 6 monthsof treatment.

ALS is not typically associated with a systemic inflammatory responseand accordingly baseline eosinophil counts in the dexpramipexole-treatedand placebo groups of 0.129 and 0.127×10⁹/L, respectively, were withinthe reference range. However, the eosinophil-lowering effect ofdexpramipexole was not diminished in subjects (n=42) with highereosinophil counts (i.e. >0.25×10⁹/L), among whom a 75% decrease wasobserved after 6 months of treatment (data not shown).

Changes in basophil counts were also analyzed in the Phase 3 trial. Asshown in FIG. 3A, basophil counts, like eosinophil counts, declinedslowly, reached plateau at about month 4, and remained reduced for theduration of treatment through month 12. At the six month analysis, meanbasophil counts were 45.5% reduced from baseline (p<0.0001).

Example 4

Effects of Dexpramipexole on ALS Clinical Trial Subjects with BaselineHypereosinophilia

Baseline parameters were reviewed in Phase 2 and Phase 3 studies ofdexpramipexole in ALS to identify subjects with significantly elevatedeosinophil counts prior to the initiation of dexpramipexole treatment.As shown in FIG. 4A, one Phase 2 subject with hypereosinophilia at Part2 baseline showed a decrease in eosinophil counts with dexpramipexoletreatment. The substantial reduction in eosinophils persisted for theperiod the subject remained on dexpramipexole through month 12.

As shown in FIG. 4B, a Phase 3 subject with elevated eosinophil countsat baseline also showed a decrease in eosinophil counts withdexpramipexole treatment. This subject had the highest baselineeosinophil count in the dexpramipexole treatment group in the Phase 3study and showed a decrease in eosinophil counts on treatment. Thesubstantial reduction in eosinophils persisted for the period thesubject remained on dexpramipexole through month 12.

Example 5

Hematological Effects of Dexpramipexole

Hematological parameters were measured in a Phase 3 study ofdexpramipexole in ALS. Because of the high rate of mortality among ALSpatients, including subjects in the Phase 3 trial, hematology parametersobtained at the month 6 visit were chosen for analysis to remove theeffect of study dropouts in later months. At month 6 in the Phase 3study, all myeloid and lymphoid cell types measured showed statisticallysignificant mean reductions from baseline, although the magnitude of theeffect was greatest for eosinophils, which declined 68.4% from baseline,and basophils, which declined 45.5% from baseline (FIG. 5). Notablyamong hematology parameters, there was no effect of dexpramipexole oneither red blood cells or platelets compared to the control group.

Example 6

Effects of Dexpramipexole on the Bone Marrow of Mice

The study consisted of 3 groups of BALB/cByJ mice (10 mice per group).Mice received daily gavage treatments of either 30 mg/kg, 100 mg/kg ofdexpramipexole or vehicle control for 70 days. Bone marrow was processedinto single cell suspensions and cells were stained with fluorescentconjugate antibodies to analyze the developmental stages of cells byflow cytometry. A. Dexpramipexole lowered the number of cell surfacemarker Sca1⁺ c-Kit⁺ cells that are lineage negative, which in the bonemarrow are multipotent hematopoietic stem cells, after treatment witheither dose compared with the vehicle control treatment group. B.Dexpramipexole lowered Siglec-F^(lo) IL5Rα^(hi) positive cells, markingdeveloping B cells, basophils and other cell populations, aftertreatment with either dose compared with the vehicle control treatmentgroup. The columns depict the mean for each group and the error barindicates the standard error of the mean. The asterisks denotestatistical significance between treatment groups and the vehiclecontrol group by one-way ANOVA (* p≤0.05, ** p≤0.01).

What is claimed is:
 1. A method of treating multiple myeloma in asubject comprising administering to the subject in need thereof atherapeutically effective amount of dexpramipexole or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, wherein thetherapeutically effective amount of dexpramipexole is from about 1 mg toabout 1,000 mg per day.
 3. The method of claim 1, wherein thetherapeutically effective amount of dexpramipexole is from about 50 mgto about 600 mg per day.
 4. The method of claim 1, wherein thetherapeutically effective amount of dexpramipexole is from about 150 mgto about 300 mg per day.
 5. The method of claim 1, wherein administeringis selected from a group consisting of administering a fraction of thetherapeutically effective amount two or more times per day,administering an amount equal to about half of the therapeuticallyeffective amount twice per day, and administering the therapeuticallyeffective amount every 12 hours.
 6. The method of claim 1, whereinadministering comprises administering about 150 mg two times per day. 7.The method of claim 1, further comprising an induction step, whereinsaid induction step is selected from a group consisting of administeringa therapeutic agent selected from the group consisting of aglucocorticoid, a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonalantibody directed against one or more pro-inflammatory cytokines, achemotherapeutic agent, a phenolic antioxidant, an anti-proliferativedrug, an anti IL-5 monoclonal antibody, an IL-5 receptor monoclonalantibody, an anti IL-13 monoclonal antibody, an anti IL-13 receptormonoclonal antibody, an anti IL-4 monoclonal antibody, an anti IL-4receptor monoclonal antibody, an anti IgE monoclonal antibody, a TNF-αinhibitor, a fusion protein, an anti-inflammatory drug, and acombination thereof.
 8. The method of claim 7, wherein the tyrosinekinase inhibitor is imatinib.
 9. The method of claim 7, wherein the antiIL-5 monoclonal antibody is selected from the group consisting ofmepolizumab and reslizumab.
 10. The method of claim 7, wherein the IL-5receptor monoclonal antibody is benralizumab.
 11. The method of claim 7,wherein the anti IL-13 monoclonal antibody is lebrikizumab.
 12. Themethod of claim 7, wherein the anti IL-4 receptor monoclonal antibody isdupilumab.
 13. The method of claim 7, wherein the anti IgE monoclonalantibody is omalizumab.
 14. The method of claim 7, wherein the TNF-αinhibitor is selected from the group consisting of infliximab,adalimumab, certolizumab pegol, and golimumab.
 15. The method of claim7, wherein the fusion protein is etanercept.
 16. The method of claim 1,wherein administering comprises administering about 75 mg two times perday.
 17. The method of claim 1, wherein administering comprisesadministering about 300 mg two times per day.
 18. The method of claim 1,wherein the therapeutically effective amount of dexpramipexole isadministered as an initial dosing regimen and then as a maintenancedosing regimen.
 19. The method of claim 18, wherein the therapeuticallyeffective amount of the initial dosing regimen is from about 50 mg toabout 1,500 mg per day.
 20. The method of claim 18, wherein thetherapeutically effective amount of the initial dosing regimen is fromabout 150 mg to about 300 mg per day.
 21. The method of claim 18,wherein the therapeutically effective amount of the initial dosingregimen is from about 300 mg to about 500 mg per day.
 22. The method ofclaim 18, wherein the therapeutically effective amount of the initialdosing regimen is from about 300 mg to about 600 mg per day.
 23. Themethod of claim 18, wherein the therapeutically effective amount of themaintenance dosing regimen is from about 50 mg to about 1,500 mg perday.
 24. The method of claim 18, wherein the therapeutically effectiveamount of the maintenance dosing regimen is from about 150 mg to about300 mg per day.
 25. The method of claim 18, wherein the therapeuticallyeffective amount of the maintenance dosing regimen is from about 300 mgto about 500 mg per day.
 26. The method of claim 18, wherein thetherapeutically effective amount of the maintenance dosing regimen isfrom about 300 mg to about 600 mg per day.
 27. The method of claim 1,wherein the therapeutically effective amount is administered orally. 28.The method of claim 1, wherein the therapeutically effective amount isadministered topically.